Life sciences · 2012
Pharmacokinetic and pharmacodynamic properties of SOL1: a novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme.
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Nelissen J, Lemkens P, Sann H, Bindl M, Bassissi F, Jasserand D, De Mey J G R, Janssen B J A
Аннотация
AIMS: The pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined.
MAIN METHODS: The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo.
KEY FINDINGS: In vitro, at neutral pH, 10 μM SOL1 inhibited NEP-1, NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC(50)s were 25, 25 and 3200 nmol/L, respectively. In anesthetized rats, SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1-31) with ED(50)s of 1.9 and 0.03 mg/kg, corresponding to plasma EC(50)s of 4.6 and 0.1 μmol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9 ml/kg.min and T(1/2) between 20 and 60 min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3 weeks at 50mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 μmol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 μmol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine.
SIGNIFICANCE: These data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model.
MAIN METHODS: The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo.
KEY FINDINGS: In vitro, at neutral pH, 10 μM SOL1 inhibited NEP-1, NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC(50)s were 25, 25 and 3200 nmol/L, respectively. In anesthetized rats, SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1-31) with ED(50)s of 1.9 and 0.03 mg/kg, corresponding to plasma EC(50)s of 4.6 and 0.1 μmol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9 ml/kg.min and T(1/2) between 20 and 60 min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3 weeks at 50mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 μmol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 μmol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine.
SIGNIFICANCE: These data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model.
Предметные рубрики MeSH
AnimalsAspartic Acid EndopeptidasesBenzazepinesBlood PressureDesoxycorticosteroneDisease Models, AnimalEndothelin-Converting EnzymesEnzyme InhibitorsHalf-LifeHumansHydrogen-Ion ConcentrationHypertensionInhibitory Concentration 50MaleMetalloendopeptidasesMiceMice, Inbred C57BLNeprilysinRatsRats, Sprague-DawleyRats, WistarSodium Chloride, DietaryTissue Distribution